1) Field of the Invention
This invention relates to a process for the production of sustained release microspheres of a drug, and especially to a process for producing, by O/W solvent evaporation, microspheres which contain a drug at high concentration.
2) Description of the Related Art
O/O, W/O/W and O/W solvent evaporation methods have heretofore been known for the formation of microspheres.
Appropriate for efficient incorporation of a drug in microspheres is O/O solvent evaporation which uses a water-miscible solvent as an inner phase and a silicone oil, vegetable oil or the like as an outer phase. This technique however involves many problems such as the use of a solvent in a large volume and the need for heating upon drying.
Japanese Patent Application Laid-Open (Kokai) No. SHO 62-201816 discloses a W/O/W solvent evaporation method, in which the viscosity of a W/O emulsion is adjusted to 150-10,000 cp for efficient incorporation of a drug. However, W/O/W type microspheres have a three-phase structure so that the process requires complex steps. It is also necessary to adjust the viscosity of the inner water phase by using gelatin or the like.
O/W solvent evaporation requires a relatively small amount of an organic solvent. When this method is applied to a water-soluble drug, most of the drug is distributed to the outer water phase. This has led to the drawback that the amount of the drug incorporated in the resulting microspheres is extremely small.
According to general O/W solvent evaporation methods, the resulting microspheres show such release behavior that the release of the drug is relatively slow in the initial stage after administration but becomes faster as time goes on.